Times series of a simulation when: (A) a double mutation never occurs; (B) the first mutation emerges from Y cell population (tmase+ first); and (C), the first mutation emerges from the W cell population (p53+/− first). In each panel, the first emergence of a double mutation is indicated by s solid dot. In panels A–C, ρe = 20, d = 0.1, and, D = 1.05. (D) Probability that the first double mutant emerges through the pathway tmase+ first followed by p53+/−. Error bars indicate 95% confidence intervals. Blue and red colors correspond to different values of the replication capacity extension ρe, defined as the number of extra division that p53+/− cells can undergo before entering crisis. Solid and dashed lines indicate different values D for the cell death of unstable cells (compared to a dimensionless division rate parameter r = 1). The maximum replication capacity of of X cells (tmase– and p53+/+) is set to ρm = 50. (E) Probability of the emergence of a double mutant. (F) Expected time of the first emergence of a double mutant. Results based on 105 − 106 simulations per data point.